A number of attempts have been made to fashion solid, bioabsorbable implant and/or dressing materials for application to wounds to protect the wounds and assist wound healing and tissue regeneration.
A solid wound implant material should preferably include the properties of gradual, controllable degradation and absorption in situ as the wound heals, low antigenicity, mechanical strength, conformability, and optimised porosity. The controlled porosity is important because the healing of wounds depends on the production by the wound of substantial quantities of matrix materials and granulation tissue involving the migration of fibroblast cells and connective tissue into the implant.
Various naturally occurring biopolymers, including proteins and polysaccharides, have been used over the last 20-30 years in the treatment of wounds or the augmentation of soft tissues. Proteins such as collagen, the most common animal protein and the main component of most connective tissues in the animal body, have been used due to their convenient physical properties and their high degree of bioacceptability. Collagen exists as many genetically distinct types, but the higher mammals share in common these types and the homology between the various types in, for example, man, cattle, sheep, pigs or chickens, is remarkably high. This means that the immunogenicity of animal collagens when implanted into humans, is very low and, therefore, that adverse reaction is very low. Furthermore, collagen and many other biopolymers actively assist wound healing by promoting the proliferation of fibroblasts, and by promoting angiogenesis.
Other proteins, especially those of the connective tissue matrix of man have been suggested as possible components of wound healing or tissue implant materials. These proteins include fibronectin, laminin and fibrin. Similarly, the high molecular weight polysaccharides of the connective tissue matrix have also been used in various types of wound dressing or "synthetic skins". These include such molecules as heparan sulphate, chondroitin sulphate, hyaluronic acid and dermatan sulphate. Other naturally occurring polysaccharide materials, especially of plant origin, have been cited as useful in the manufacture of dressings for wounds (e.g. alginates, guar gum, various plant gums) although not, in the main, in fabrication of implants as they are not bioabsorbable.
U.S. Pat. No. 4,970,298 (Frederick H. Silver et al) describes a biodegradable collagen matrix allegedly suitable for use as a wound implant. The matrix is formed by freeze drying an aqueous dispersion containing collagen, cross-linking the collagen via two cross-linking steps and freeze-drying the cross-linked matrix. The matrix may also contain hyaluronic acid and fibronectin.
EP-A-0274898 (Ethicon Inc.) describes an absorbable implant material having an open cell, foam-like structure and formed from resorbable polyesters, such as poly-p-dioxanone, other polyhydroxycarboxylic acids, polylactides or polyglycolides. The open-cell plastic matrix is reinforced with one or more reinforcing elements of a textile nature formed from a resorbable plastic and embedded in the matrix. The open-cell plastic matrix is made by freeze-drying a solution or suspension of the plastic material in a non-aqueous solvent. The pore size of the open-cell plastic matrix is from 10 to 200 .mu.m.
JP-A-03023864 (Gunze KK) describes a wound implant material comprising a collagen sponge matrix reinforced with fibres of poly-L-lactic acid. The collagen sponge matrix is formed by freeze drying a solution of porcine atherocollagen.
EP-A-0562862 (Johnson & Johnson Medical, Inc.) describes bioabsorbable wound implant materials that are composites comprising a collagen sponge matrix having embedded therein oriented substructures of solid collagen fibers, films or flakes. The substructures reinforce the collagen sponge and also provide a scaffold for directional cellular migration into the implant. The composites are formed by immersing the substructures in an aqueous collagen slurry and then freeze-drying the slurry to form the collagen sponge matrix.
The above bioabsorbable sponge implants are formed by freeze-drying or solvent drying solutions or suspensions of a bioabsorbable material in a solvent. However, it is generally difficult to control the pore size and density of sponge materials made in this way. The structural integrity of these sponges has been enhanced by embedding bioabsorbable reinforcing fibres or substructures in the sponge matrix. The resorption of the sponges has been slowed by chemical cross-linking of the biopolymer.
Attempts have also been made to reduce the pore size of collagen sponges formed by freeze-drying. This was done in order both to increase the density of the sponges and to limit the pore size to the 50-250 .mu.m range that was thought to be optimum for invasion by fibroblasts.
In particular, WO90/00060 (Collagen Corporation) describes collagen implants that are formed by flash freezing and then freeze-drying a suspension of collagen fibrils without chemical cross-linking. The flash freezing results in smaller ice crystals, and hence in smaller pores in the finished sponge. The implants have a bulk density of 0.01 to 0.3 g/cm.sup.3 and a pore population in which at least about 80% of the pores have an average pore size of 35 to 250 .mu.m. This wound healing matrix also serves as an effective sustained delivery system for bioactive agents.
Many of these sponge materials are intended for use in tissue augmentation or repair and require to be invaded and replaced by cells and newly synthesised connective tissue. In this regard, it is crucial that a material placed into a wound to replace lost tissue, or used to augment deficient tissue, should be rapidly colonised by cells and newly forming connective tissue. If this does not happen, the material will be rapidly exfoliated by the wound bed and granulation tissue which will form outside of the matrix.
It has now been found that larger pores, in the size range 0.1-3.0, preferably 0.3-1.0 mm, enhance fibroblast invasion rates and result in enhanced wound healing properties.
Wake et al in Cell Transplantation vol. 3(4), pp 339-343 (1994) describe studies of pore size effects on the fibrovascular tissue growth in porous bioabsorbable polymer substrates. The substrates of poly-L-lactic acid (PLLA) were prepared with pore sizes of up to 500 .mu.m by a particulate leaching technique. Briefly, the PLLA was dissolved in methylene chloride and sieved sodium chloride particles having diameters similar to the desired pore size were dispersed in the solution. The resulting dispersion was then cast into disks and dried. The sodium chloride was then leached from the disks to leave the desired porous PLLA structure. It was found that fibrovascular tissue advances much faster into porous PLLA with a larger pore size (.about.500 .mu.m) than into porous PLLA having smaller pores (179 and 91 .mu.m).
Mikos et al in Polymer vol. 35(5), pages 1068-1077 (1994) describe the preparations of PLLA sponges by particulate leaching in more detail. They state that, when 70-90% by weight of sodium chloride particles is included in the PLLA, the resulting leached material is homogeneous with interconnected pores. There is no disclosure of leaching the sodium chloride from frozen aqueous dispersions of PLLA.